The role of tyrosine 71 in modulating the flap conformations of BACE1

Citations Over Time

Abstract

β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is a potential target for treating Alzheimer's disease. BACE1's binding site is partially covered by a flexible loop on its N-terminal domain, known as the "flap," which has been found in several conformations in crystal structures of BACE1 and other aspartyl proteases. The side chain of the invariant residue Tyr71 on the flap adopts several rotameric orientations, leading to our hypothesis that the orientation of this residue dictates the movement and conformations available to the flap. We investigated this hypothesis by performing 220 ns of molecular dynamics simulations of bound and unbound wild-type BACE1 as well as the unbound Y71A mutant. Our findings indicate that the flap exhibits various degrees of mobility and adopts different conformations depending on the Tyr71 orientation. Surprisingly, the "self-inhibited" form is stable in our simulations, making it a reasonable target for drug design. The alanine mutant, lacking a large side chain at position 71, displays significant differences in flap dynamics from wild type, freely sampling very open and closed conformations. Our simulations show that Tyr71, in addition to its previously determined functions in catalysis and substrate binding, has the important role of modulating flap conformations in BACE1.

Related Papers

• → Synthetic Approaches for the Construction of Five- and Six-Membered Silaazacycles(2022)15 cited
• → Guadinomines, Type III Secretion System Inhibitors, Produced by Streptomyces sp. K01-0509(2008)44 cited
• → Synthesis and Shuttling Behavior of [2]Rotaxanes with a Pyrrole Moiety(2016)26 cited
• Design, synthesis and evaluation of novel hydroxyethylamine derivatives with nitrogen heterocyclic moiety at N-terminal as BACE1 inhibitors(2010)
• STUDY ON INTRAMOLECULAR SYNERGISTIC INHIBITIVE EFFECTS OF BENZOTRIAZOLY MOIETY AND INIDAZOLY MOIETY(2009)